This is project seeks to understand the relationships between brain function, neuroticism and mood and cognitive outcomes in late life depression. Neuroticism is a clinical phenomenon commonly observed in depression across the life span. Less clear are the mood and cognitive consequences of Neuroticism in older depressed adults. Further, there is only limited understanding of biological processes related to Neuroticism at any age. These questions are particularly meaningful in late life depression, which is itself associated with increased risk of poor outcomes, including lower remission rates, higher relapse rates and increased risk of incident dementia. Identification of factors related to these poor outcomes is essential for preventing the morbidity associated with persistent depression and cognitive decline and for development of neurally informed novel interventions. In our preliminary data, we used functional magnetic resonance imaging (fMRI) to calculate resting state functional connectivity (rsFC) between key seed brains regions and other regions. We found associations between ventromedial prefrontal cortex and the hippocampus, between the left orbitofrontal cortex and the amygdala, and the right dorsal anterior cingulate cortex and the right posterior cingulate cortex. We also found that higher Neuroticism in older depressed subjects was associated with higher depression scores and greater cognitive decline over time. We propose to recruit 140 older depressed patients and 75 older non-depressed controls. Detailed psychosocial, functional, clinical, psychiatric, medical, neurological, and cognitive assessments will be obtained at baseline and at defined points during follow-up. Structural and function MRI studies will be performed. The principal outcome measures are trajectory of mood and cognition and neural correlates of neuroticism. All patients will receive standardized treatment for up to 24 weeks with a standardized two-step intervention using citalopram followed by either bupropion augmentation or desvenlafaxine. After 24 weeks, subjects will be followed using an established guideline-based treatment algorithm. The analysis plan focuses on examining 1) neural links (based on fMRI rsFC) associated Neuroticism; 2) longitudinal mood and cognitive consequences of Neuroticism among older depressed patients; 3) whether the clinical adverse mood and cognitive outcomes of depression are mediated by specific brain changes seen on fMRI. It is expected that results from this study will identify brain regions involved in Neuroticism and will clarify the relationship between Neuroticism and poor outcomes in depressed elderly. PUBLIC HEALTH RELEVANCE: Presence of neuroticism predicts poor outcomes of depression, yet little is known about its biological basis. Depression in late life is a risk facto for cognitive decline and dementia. This study seeks to further our scientific understanding of the complex relationships among depression, neuroticism, persistent depression and cognitive impairment. We aim to identify older depressed adults who are at risk for negative outcomes.